Adalat® XL®
Nifedipine
Antianginal--Antihypertensive
Bayer
http://www.pharma.bayer.com/en/home.html
Adalat Monograph PDF download here.
Description
System Components and Performance:
Adalat XL extended release tablets, while similar in appearance to a
conventional tablet, nonetheless consist of a semipermeable membrane
surrounding an osmotically active drug core. The core itself is divided into
2 layers: an “active” layer containing the drug, and a “push” layer containing
pharmacologically inert, but osmotically active components. As water from the
gastrointestinal tract enters the tablet, pressure increases in the osmotic
layer and “pushes” against the drug layer, forcing drug through the orifice in
the active layer.
Drug delivery is
essentially constant as long as the osmotic gradient remains constant, and then
gradually falls to zero as drug is exhausted from the tablet. Upon swallowing,
the biologically inert components of the tablet remain intact during gastrointestinal
transit and are eliminated in the feces as an insoluble shell.CPS:PIS_m007200
Pharmacology
Nifedipine is a calcium ion influx inhibitor
(calcium channel blocker or calcium ion antagonist).
The antianginal and
antihypertensive actions of nifedipine are believed to be related to a specific
cellular action of selectively inhibiting transmembrane influx of calcium ions
into cardiac muscle and vascular smooth muscle. The contractile processes of
these tissues are dependent upon the movement of extracellular calcium into the
cells through specific ion channels. Nifedipine selectively inhibits the
transmembrane influx of calcium through the slow channel without affecting, to
any significant degree, the transmembrane influx of sodium through the fast
channel. This results in a reduction of free calcium ions available within the
muscle cells and an inhibition of the contractile processes. Nifedipine does
not alter total serum calcium.
The specific mechanisms
by which nifedipine relieves angina and reduces blood pressure have not been
fully determined but are believed to be brought about largely by its
vasodilatory action.
Nifedipine dilates the
main coronary arteries and coronary arterioles both in normal and ischemic
regions resulting in an increase in blood flow and hence in myocardial oxygen
delivery.
Nifedipine by its
vasodilatory action on peripheral arterioles, reduces the total peripheral
vascular resistance. This reduces the workload of the heart and thus reduces
myocardial energy consumption and oxygen requirements which probably accounts
for the effectiveness of nifedipine in chronic stable angina.
The mechanism by which
nifedipine reduces arterial blood pressure involves peripheral arterial
vasodilation and subsequent reduction in peripheral vascular resistance. The
increased peripheral vascular resistance that is an underlying cause of
hypertension results from an increase in active tension in the vascular smooth
muscle. Studies have demonstrated that the increase in active tension reflects
an increase in cytosolic free calcium.
The negative inotropic
effect of nifedipine is usually not of major clinical significance because at
therapeutic doses, nifedipine's vasodilatory property evokes a baroreceptor
mediated reflex tachycardia which tends to counterbalance this negative
inotropic effect. Continued administration of nifedipine to hypertensive
patients has shown no significant increase in heart rate.
Although nifedipine
causes a slight depression of sinoatrial node function and AV conduction in
isolated myocardial preparations, such effects have not been seen in studies in
intact animals or in man. In formal electrophysiologic studies, predominantly
in patients with normal conduction systems, nifedipine has had no tendency to
prolong AV conduction or sinus node recovery time, or to slow sinus rate.
The International
Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment trial
called INSIGHT was a prospective double-blind trial with dynamic randomisation
which enrolled mainly white hypertensive men and women. The primary endpoint
was a composite of death from any cardiovascular or cerebrovascular cause,
together with non-fatal stroke, myocardial infarction, and heart failure. The
secondary endpoint included total mortality, death from a vascular cause, and
non-fatal vascular events including transient ischemic attacks, angina (new or
worsening) and renal failure. INSIGHT was designed to establish the superiority
of Adalat XL over the diuretic combination co-amilozide (hydrochlorothiazide
and amiloride). When the results of the Swedish Trial in Old Patients with
Hypertension-2 study (STOP-2) became known and because these results suggested
that calcium-channel blockade and diuretic treatment had similar efficacy in
preventing complications, but before the patient code in INSIGHT was broken, a
secondary, non-inferiority analysis was added.
INSIGHT randomized 6575
mild to moderate essential hypertensive or isolated systolic hypertensive
patients, 55 – 80 years of age, with at least one other cardiovascular risk
factor to nifedipine and co-amilozide. Patients were excluded if they had heart
failure with low ejection fraction (< 40%), unstable angina, PTCA
(Percutaneous Transluminal Coronary Angioplasty) or CABG (Coronary Artery
Bypass Grafting) within 6 months prior to study start, or myocardial infarction
or stroke in the 12 months prior to study start. Doses of each drug were
titrated to achieve a target blood pressure of 140/90 mmHg (or drop of 20/10
mmHg) and if that target was not reached additional drugs could be added
(atenolol and subsequently enalapril). On average patients were treated for 3.5
years. After placebo washout, the baseline blood pressure was 173/99 mmHg and
decreased to 138/82 mmHg by the end of the trial in both groups. Heart rate was
not different between the groups. At the end of the study 69 and 72% of
patients on Adalat XL and hydrochlorothiazide/amiloride, respectively, were on
monotherapy. All endpoints were assessed and adjudicated by the Critical Events
Committee. The overall results of the study in Table 1 show that Adalat XL was
not inferior to the diuretic combination co-amilozide.
CPS:AdalatXL_t1Click here for Table 1
Table 1: Adalat XL
Results of the INSIGHT Study
|
|
Adalat XL
|
Hydrochlorothiazide/Amiloride
|
Odds Ratio (95% CI)
|
p-value
|
|
Primary Outcomes Composite
|
200 (6.3%)
|
182 (5.8%)
|
1.11 (0.90–1.36)
|
0.34
|
|
Secondary Outcomes Composite
|
383 (12.1%)
|
397 (12.5%)
|
0.96 (0.83–1.12)
|
0.62
|
|
Total Mortality
|
153 (4.8%)
|
152 (4.8)
|
1.01 (0.80–1.27)
|
0.95
|
|
All Adverse Events
|
1546 (49%)
|
1327 (42%)
|
N/A
|
< 0.001
|
|
Serious Adverse Events
|
796 (25%)
|
880 (28%)
|
N/A
|
0.02
|
Pharmacokinetics
Nifedipine is completely absorbed after oral
administration. Plasma drug concentrations rise at a gradual, controlled rate
exhibiting zero-order absorption kinetics after nifedipine administration and
reach a plateau at approximately 6 hours after the first dose. For
subsequent doses, relatively constant plasma concentrations at this plateau are
maintained with minimal fluctuations over the 24-hour dosing interval. About a
4-fold higher fluctuation index (ratio of peak to trough plasma concentration) was
observed with the conventional immediate release Adalat capsule at t.i.d.
dosing than with once daily Adalat XL tablets. At steady state the
bioavailability of the Adalat XL tablet is 86% relative to Adalat
capsules. Administration of the Adalat XL tablet in the presence of food
slightly alters the early rate of drug absorption, but does not influence the
extent of drug bioavailability. Markedly reduced gastrointestinal retention
time over prolonged periods (i.e., short bowel syndrome), however, may influence
the pharmacokinetic profile of the drug which could potentially result in lower
plasma concentrations. Pharmacokinetics of Adalat XL tablets are linear
over the dose range of 30 to 180 mg in that plasma drug
concentrations are proportional to dose administered. There was no evidence of
dose dumping either in the presence or absence of food. The bioavailability of
the 20 mg tablet is directly proportional to the 30 mg tablet.
Nifedipine is
extensively metabolized to highly water-soluble, inactive metabolites
accounting for 60 to 80% of the dose excreted in the urine. The
remainder is excreted in the feces in metabolized form, most likely as a result
of biliary excretion. The main metabolite (95%) is the hydroxycarbolic acid
derivative, the remaining 5% is the corresponding lactone. Only traces
(less that 0.1% of the dose) of unchanged nifedipine can be detected in
the urine. Thus, the pharmacokinetics of nifedipine are not significantly
influenced by the degree of renal impairment. Patients in hemodialysis or CAPD
(continuous ambulatory peritoneal dialysis) have not reported significantly
altered pharmacokinetics of nifedipine.
Since hepatic
biotransformation is the predominant route for the disposition of nifedipine,
the pharmacokinetics may be altered in patients with chronic liver disease.
Pharmacokinetic studies in patients with hepatic cirrhosis showed a clinically
significant prolongation of elimination half-life and a decrease in total
clearance of nifedipine. The degree of serum protein binding of nifedipine is
high (92 to 98%). Protein binding may be greatly reduced in patients
with renal or hepatic impairment (see Precautions).
Nifedipine is
metabolized by the cytochrome P450 enzyme system, predominantly via CYP3A4, but
also by CYP1A2 and CYP2A6 isoenzymes.
Compounds found in
grapefruit juice inhibit the cytochrome P450 system, especially CYP3A4. In a
grapefruit juice-nifedipine interaction study in healthy male volunteers,
pharmacokinetics of nifedipine showed significant alteration. Following
administration of a single dose of nifedipine 10 mg with 250 mL of
grapefruit juice, the mean value of nifedipine AUC increased by 34% and the tmax
increased from 0.8 to 1.2 hours, as compared to water (see
Precautions, Interaction With Grapefruit Juice).
Indications
Chronic Stable Angina: In the management of
chronic stable angina (effort-associated angina) without evidence of vasospasm
in patients who remain symptomatic despite adequate doses of beta-blockers
and/or nitrates, or who cannot tolerate these agents.
May be used in
combination with beta-blocking drugs in patients with chronic stable angina.
However, available information is not sufficient to predict with confidence the
effects of concurrent treatment, especially in patients with compromised left
ventricular function or cardiac conduction abnormalities. When introducing such
concomitant therapy, care must be taken to monitor blood pressure closely,
since severe hypotension can occur from the combined effects of the drugs (see
Warnings).
Hypertension: In the management of mild to
moderate essential hypertension. Should normally be used in those patients in
whom treatment with diuretics or beta-blockers has been ineffective, or has
been associated with unacceptable adverse effects.
It can be tried as an
initial agent in those patients in whom the use of diuretics and/or
beta-blockers is contraindicated, or in patients with medical conditions in
which these drugs frequently cause serious adverse effects.
Combination of
Adalat XL with a diuretic has been found compatible and has shown added
antihypertensive effect. Concurrent administration of low doses of Adalat XL
and enalapril has been shown to produce an enhanced antihypertensive effect
with no additional safety concerns when compared to that observed with either
of the monotherapies.
Safety of concurrent
use of Adalat XL with other antihypertensive agents has not been
established.
Contraindications
Pregnancy
Nifedipine is contraindicated in pregnancy,
during lactation, and in women of childbearing potential. Fetal malformations
and adverse effects on pregnancy have been reported in animals.
An increase in the
number of fetal mortalities and resorptions occurred after the administration
of 30 and 100 mg/kg of nifedipine to pregnant mice, rats and
rabbits. Fetal malformations occurred after the administration
of 30 and 100 mg/kg nifedipine to pregnant mice and
100 mg/kg to pregnant rats.
Lactation
See Pregnancy.
In patients with
hypersensitivity to nifedipine.
In patients with severe
hypotension.
Warnings
Excessive Hypotension in Patients With Angina:
Since nifedipine lowers peripheral vascular resistance and blood pressure, it
should be used cautiously in patients with angina who are prone to develop
hypotension and those with a history of cerebrovascular insufficiency.
Occasional patients have had excessive and poorly tolerated hypotension.
Syncope has been reported (see Adverse Effects). These responses have usually
occurred during initial titration or at the time of subsequent upward dosage
adjustment, and may be more likely in patients on concomitant beta-blockers. If
excessive hypotension occurs, dosage should be lowered or the drug should be
discontinued (see Contraindications).
Severe hypotension
and/or increased fluid volume requirements have been reported in patients
receiving nifedipine, with a beta-blocker, who underwent coronary artery bypass
surgery using high dose fentanyl anesthesia. The interaction with high dose
fentanyl appears to be due to the combination of nifedipine and a beta-blocker,
but the possibility that it may occur with nifedipine alone, with low doses of
fentanyl in other surgical procedures, or with other narcotic analgesics cannot
be ruled out. In nifedipine-treated patients where surgery using high dose
fentanyl anesthesia is contemplated, the physician should be aware of these
potential problems and if the patient's condition permits, sufficient time (at
least 36 hours), should be allowed for nifedipine to be washed out of the
body prior to surgery.
The following
information should be taken into account in those patients who are being
treated for hypertension as well as angina.
Increased Angina and/or Myocardial Infarction:
Rarely, patients, particularly those who have severe obstructive coronary
artery disease have developed well-documented increased frequency, duration
and/or severity of angina or acute myocardial infarction on starting nifedipine
or at the time of dosage increase. The mechanism of the response is not
established.
Since there has not
been a study of Adalat XL in acute myocardial infarction reported, similar
effects of Adalat XL to that of immediate-release nifedipine cannot be
excluded. Immediate-release nifedipine is contraindicated in acute myocardial
infarction.
Beta-blocker Withdrawal: Patients with angina
recently withdrawn from beta-blockers may develop a withdrawal syndrome with
increased angina, probably related to increased sensitivity to catecholamines.
Initiation of treatment with nifedipine will not prevent this occurrence and
might be expected to exacerbate it by provoking reflex catecholamine release.
There have been occasional reports of increased angina in a setting of
beta-blocker withdrawal and initiation of nifedipine. It is important to taper
beta-blockers if possible, rather than stopping them abruptly before beginning
nifedipine.
Patients with Heart Failure: There have been
isolated reports of severe hypotension and lowering of cardiac output following
administration of nifedipine to patients with severe heart failure. Thus,
nifedipine should be used cautiously in patients with severe heart failure.
Rarely, patients usually receiving a beta-blocker, have developed heart failure
after beginning nifedipine therapy.
In patients with severe
aortic stenosis, nifedipine will not produce its usual afterload reducing
effects and there is a possibility that an unopposed negative inotropic action
of the drug may produce heart failure if the end-diastolic pressure is raised. Caution
should therefore be exercised when using nifedipine in patients with these
conditions.
Patients with Pre-existing Gastrointestinal
Narrowing: Since the Adalat XL delivery system contains a nondeformable
material, caution should be used when administering it in patients with
pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic).
There have been rare reports of obstructive symptoms in patients with known
strictures in association with the ingestion of Adalat XL tablets.
Precautions
Hypotension/Heart Rate: Because nifedipine is an
arterial and arteriolar vasodilator, hypotension and a compensatory increase in
heart rate may occur. Thus, blood pressure and heart rate should be monitored
carefully during nifedipine therapy. Close monitoring is especially recommended
for patients who are prone to develop hypotension, those with a history of
cerebrovascular insufficiency, and those who are taking medications that are
known to lower blood pressure (see Warnings).
Peripheral Edema: Mild to moderate peripheral
edema, typically associated with arterial vasodilation and not due to left
ventricular dysfunction, has been reported to occur in patients treated with
nifedipine (see Adverse Effects). This edema occurs primarily in the lower
extremities and may respond to diuretic therapy. With patients whose angina or
hypertension is complicated by congestive heart failure, care should be taken
to differentiate this peripheral edema from the effects of increasing left
ventricular dysfunction.
Male Fertility: In some cases of in vitro
fertilization, nifedipine has been associated with reversible spermatozoal
biochemical changes. In vitro studies have shown that nifedipine may inhibit
expression of mannose-ligand receptors, thus preventing the spermatozoa from
attaching to the zona pellucida and impairing sperm function. In those men who
are repeatedly unsuccessful in fathering a child by in vitro fertilization, and
where no other explanation could be found, nifedipine should be considered as a
possible cause.
Geriatrics
Nifedipine should be administered cautiously to
elderly patients, especially to those with a history of hypotension or cerebral
vascular insufficiency.
Diabetic Patients: The use of nifedipine in
diabetic patients may require adjustment for their control.
Patients With Impaired Liver Function:
Nifedipine should be used with caution in patients with impaired liver function
(see Pharmacology). A dose reduction, particularly in severe cases, may be
required. Close monitoring of response and metabolic effect sh
